Objective: To examine the relation between plasma concentrations of interleukin-18 (IL-18), the i... more Objective: To examine the relation between plasma concentrations of interleukin-18 (IL-18), the interferon γ inducing factor, and clinical instability of coronary artery disease.Design and setting: Observational study in a university hospital.Patients: 11 patients with unstable angina and negative troponin I, 21 patients with acute non-Q wave myocardial infarction (MI), 21 patients with acute Q wave MI, 9 patients with stable
The role of vascular cells during inflammation is critical and is of particular importance in inf... more The role of vascular cells during inflammation is critical and is of particular importance in inflammatory diseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the IkB/nuclear factor-kB system.
Interleukin (IL)-18 is the interferon- g-inducing factor and has other proinflammatory properties... more Interleukin (IL)-18 is the interferon- g-inducing factor and has other proinflammatory properties. The precise role of IL-18 in immunoinflammatory diseases remains poorly understood. In this study, we show that in vivo electrotransfer of an expression-plasmid DNA encoding for murine IL-18 binding protein (BP) (the endogenous inhibitor of IL-18) prevents fatty streak development in the thoracic aorta of apoE knockout mice
Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial bl... more Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded
Intravascular hemolysis describes the relocalization of heme and hemoglobin from erythrocytes to ... more Intravascular hemolysis describes the relocalization of heme and hemoglobin from erythrocytes to plasma. We investigated the concept that erythrocyte membrane microparticles (MP) concentrate cell-free heme in human hemolytic diseases, and that heme-laden MP have a physiopathological impact. Up to one third of cell-free heme in plasma from 47 patients with sickle cell disease (SCD) was sequestered in circulating MP. Erythrocyte vesiculation in vitro produced MP loaded with heme. In silico analysis predicted that externalized phosphatidylserine in MP may associate with and help retain heme at the cell surface. Immunohistology identified hemoglobin-laden MP adherent to capillary endothelium in kidney biopsies from hyperalbuminuric SCD patients. In addition, heme-laden erythrocyte MP adhered and transferred heme to cultured endothelial cells, inducing oxidative stress and apoptosis. In transgenic SAD mice, infusion of heme-laden MP triggered rapid vaso-occlusions in kidneys, and comprom...
Arteriosclerosis, thrombosis, and vascular biology, 2015
Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive imm... more Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins and components of the injured vascular wall. Specific T lymphocyte responses driven by T helper-1 or T regulatory cells play distinct and opposing roles in atherosclerosis. More recently, T helper-17 cells, which produce the prototype cytokine interleukin-17, have been characterized and shown to be critical in mucosal host defense against microbial and fungal pathogens. Sustained production of interleukin-17 in an inflammatory context has been linked to the pathology of several autoimmune and inflammatory diseases. However, regulatory and protective roles have also been reported in selective disease settings. Studies in atherosclerosis led to conflicting results on the roles of interleukin-17 and T helper-17 cells in disease development and plaque stability. The present review provides a summary of the available evidence and putative mechanisms link...
Adipose tissue development and remodeling are closely associated with the growth of vascular netw... more Adipose tissue development and remodeling are closely associated with the growth of vascular network. We hypothesized that adipose tissue may contain progenitor cells with angiogenic potential and that therapy based on adipose tissue-derived progenitor cells administration may constitute a promising cell therapy in patients with ischemic disease. In mice, cultured stromal-vascular fraction (SVF) cells from adipose tissue have a great proangiogenic potential, comparable to that of bone marrow mononuclear cells in the mouse ischemic hindlimb model. Similarly, cultured human SVF cells differentiate into endothelial cells, incorporate into vessels, and promote both postischemic neovascularization in nude mice and vessel-like structure formation in Matrigel plug. In vitro, these cells represent a homogeneous population of CD34- and CD13-positive cells, which can spontaneously express the endothelial cell markers CD31 and von Willebrand factor when cultured in semisolid medium. Interestin...
Members of the Rho family of small GTPases have been recently implicated in inflammatory signalin... more Members of the Rho family of small GTPases have been recently implicated in inflammatory signaling. We examined the effect of in vivo inhibition of Rho kinase on atherogenesis in mice. Low-density lipoprotein receptor (LDLR) knockout (KO) mice fed a cholate-free high-fat diet received daily intraperitoneal injection of saline (n=8, control group) or Y-27632 (30 mg/kg, n=9), a specific Rho kinase inhibitor. After 9 weeks, Y-27632 treatment resulted in significant in vivo inhibition of Rho kinase activity (P=0.004). Body weights, arterial blood pressures, and plasma cholesterol levels were comparable in both groups. Atherosclerotic lesion size in the aortic sinus and thoracic aorta of mice treated with Y-27632 was reduced by respectively 35% and 29% in comparison with the saline-treated animals (P=0.006 and P=0.03, respectively). This was associated with a significant reduction in T lymphocyte accumulation (P=0.035) and expression of p65 subunit of NF-kappaB within plaques (P<0.05)...
We investigated whether circulating procoagulant microparticles (CPMPs) contributed to hypercoagu... more We investigated whether circulating procoagulant microparticles (CPMPs) contributed to hypercoagulability in 45 patients with acute pulmonary embolism (APE) and in 45 controls with and 45 controls without cardiovascular risk factors. Concentrations of CPMPs and platelet-derived microparticles (PMPs) were statistically significantly higher in patients with APE than in controls without cardiovascular risk factors. PMPs appeared to be the main source of
Phospholipases A2 (PLA2) belong to a superfamily of enzymes that catalyze the hydrolysis of glyce... more Phospholipases A2 (PLA2) belong to a superfamily of enzymes that catalyze the hydrolysis of glycerophospholipids at the sn-2 position, producing nonesterified fatty acids and lysophospholipids. Many experimental studies have shown that PLA2 are involved in lipid metabolism and immuno-inflammatory response and participate in the development of atherosclerosis. In humans, therapeutic approaches based on the inhibition of PLA2 are currently in development. This review summarizes human studies regarding the prognostic value of two members of the family of PLA2, Lp-PLA2 (lipoprotein-associated PLA2) and sPLA2 (secretory PLA2), in cardiovascular diseases.
Objectives—Inflammatory macrophage apoptosis is critical to atherosclerotic plaque formation, but... more Objectives—Inflammatory macrophage apoptosis is critical to atherosclerotic plaque formation, but its mechanisms remain enigmatic. We hypothesized that inhibitor of apoptosis protein (IAP) survivin regulates macrophage death in atherosclerosis. Methods and Results—Western blot analysis revealed discrete survivin expression in human aorta lipid streaks but virtually none in advanced atherosclerotic plaques, despite increased XIAP and cIAP2 levels. Survivin was detected in CD68-positive
Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metaboli... more Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of
Objective—To assess the association between secretory phospholipase A2 (sPLA2) activity, which en... more Objective—To assess the association between secretory phospholipase A2 (sPLA2) activity, which encompasses several types of sPLA2, and cardiovascular disease (CAD) in healthy individuals. Methods and Results—We investigated this association in a nested case-control study among the 25 663 participants in EPIC-Norfolk cohort. Cases (n991) were subjects in whom CAD developed during the 6 years of mean follow-up. Controls (n1806) matched
Different forms of mechanical stimulation are among the physiological factors constantly acting o... more Different forms of mechanical stimulation are among the physiological factors constantly acting on the vessel wall. We previously demonstrated that subjecting vascular smooth muscle cells (VSMCs) in culture to cyclic stretch increased the expression of high-molecular-weight caldesmon, a marker protein of a differentiated, contractile, VSMC phenotype. In the present work the effects of mechanical factors, in the form of circumferential
Objective: To examine the relation between plasma concentrations of interleukin-18 (IL-18), the i... more Objective: To examine the relation between plasma concentrations of interleukin-18 (IL-18), the interferon γ inducing factor, and clinical instability of coronary artery disease.Design and setting: Observational study in a university hospital.Patients: 11 patients with unstable angina and negative troponin I, 21 patients with acute non-Q wave myocardial infarction (MI), 21 patients with acute Q wave MI, 9 patients with stable
The role of vascular cells during inflammation is critical and is of particular importance in inf... more The role of vascular cells during inflammation is critical and is of particular importance in inflammatory diseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the IkB/nuclear factor-kB system.
Interleukin (IL)-18 is the interferon- g-inducing factor and has other proinflammatory properties... more Interleukin (IL)-18 is the interferon- g-inducing factor and has other proinflammatory properties. The precise role of IL-18 in immunoinflammatory diseases remains poorly understood. In this study, we show that in vivo electrotransfer of an expression-plasmid DNA encoding for murine IL-18 binding protein (BP) (the endogenous inhibitor of IL-18) prevents fatty streak development in the thoracic aorta of apoE knockout mice
Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial bl... more Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded
Intravascular hemolysis describes the relocalization of heme and hemoglobin from erythrocytes to ... more Intravascular hemolysis describes the relocalization of heme and hemoglobin from erythrocytes to plasma. We investigated the concept that erythrocyte membrane microparticles (MP) concentrate cell-free heme in human hemolytic diseases, and that heme-laden MP have a physiopathological impact. Up to one third of cell-free heme in plasma from 47 patients with sickle cell disease (SCD) was sequestered in circulating MP. Erythrocyte vesiculation in vitro produced MP loaded with heme. In silico analysis predicted that externalized phosphatidylserine in MP may associate with and help retain heme at the cell surface. Immunohistology identified hemoglobin-laden MP adherent to capillary endothelium in kidney biopsies from hyperalbuminuric SCD patients. In addition, heme-laden erythrocyte MP adhered and transferred heme to cultured endothelial cells, inducing oxidative stress and apoptosis. In transgenic SAD mice, infusion of heme-laden MP triggered rapid vaso-occlusions in kidneys, and comprom...
Arteriosclerosis, thrombosis, and vascular biology, 2015
Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive imm... more Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins and components of the injured vascular wall. Specific T lymphocyte responses driven by T helper-1 or T regulatory cells play distinct and opposing roles in atherosclerosis. More recently, T helper-17 cells, which produce the prototype cytokine interleukin-17, have been characterized and shown to be critical in mucosal host defense against microbial and fungal pathogens. Sustained production of interleukin-17 in an inflammatory context has been linked to the pathology of several autoimmune and inflammatory diseases. However, regulatory and protective roles have also been reported in selective disease settings. Studies in atherosclerosis led to conflicting results on the roles of interleukin-17 and T helper-17 cells in disease development and plaque stability. The present review provides a summary of the available evidence and putative mechanisms link...
Adipose tissue development and remodeling are closely associated with the growth of vascular netw... more Adipose tissue development and remodeling are closely associated with the growth of vascular network. We hypothesized that adipose tissue may contain progenitor cells with angiogenic potential and that therapy based on adipose tissue-derived progenitor cells administration may constitute a promising cell therapy in patients with ischemic disease. In mice, cultured stromal-vascular fraction (SVF) cells from adipose tissue have a great proangiogenic potential, comparable to that of bone marrow mononuclear cells in the mouse ischemic hindlimb model. Similarly, cultured human SVF cells differentiate into endothelial cells, incorporate into vessels, and promote both postischemic neovascularization in nude mice and vessel-like structure formation in Matrigel plug. In vitro, these cells represent a homogeneous population of CD34- and CD13-positive cells, which can spontaneously express the endothelial cell markers CD31 and von Willebrand factor when cultured in semisolid medium. Interestin...
Members of the Rho family of small GTPases have been recently implicated in inflammatory signalin... more Members of the Rho family of small GTPases have been recently implicated in inflammatory signaling. We examined the effect of in vivo inhibition of Rho kinase on atherogenesis in mice. Low-density lipoprotein receptor (LDLR) knockout (KO) mice fed a cholate-free high-fat diet received daily intraperitoneal injection of saline (n=8, control group) or Y-27632 (30 mg/kg, n=9), a specific Rho kinase inhibitor. After 9 weeks, Y-27632 treatment resulted in significant in vivo inhibition of Rho kinase activity (P=0.004). Body weights, arterial blood pressures, and plasma cholesterol levels were comparable in both groups. Atherosclerotic lesion size in the aortic sinus and thoracic aorta of mice treated with Y-27632 was reduced by respectively 35% and 29% in comparison with the saline-treated animals (P=0.006 and P=0.03, respectively). This was associated with a significant reduction in T lymphocyte accumulation (P=0.035) and expression of p65 subunit of NF-kappaB within plaques (P<0.05)...
We investigated whether circulating procoagulant microparticles (CPMPs) contributed to hypercoagu... more We investigated whether circulating procoagulant microparticles (CPMPs) contributed to hypercoagulability in 45 patients with acute pulmonary embolism (APE) and in 45 controls with and 45 controls without cardiovascular risk factors. Concentrations of CPMPs and platelet-derived microparticles (PMPs) were statistically significantly higher in patients with APE than in controls without cardiovascular risk factors. PMPs appeared to be the main source of
Phospholipases A2 (PLA2) belong to a superfamily of enzymes that catalyze the hydrolysis of glyce... more Phospholipases A2 (PLA2) belong to a superfamily of enzymes that catalyze the hydrolysis of glycerophospholipids at the sn-2 position, producing nonesterified fatty acids and lysophospholipids. Many experimental studies have shown that PLA2 are involved in lipid metabolism and immuno-inflammatory response and participate in the development of atherosclerosis. In humans, therapeutic approaches based on the inhibition of PLA2 are currently in development. This review summarizes human studies regarding the prognostic value of two members of the family of PLA2, Lp-PLA2 (lipoprotein-associated PLA2) and sPLA2 (secretory PLA2), in cardiovascular diseases.
Objectives—Inflammatory macrophage apoptosis is critical to atherosclerotic plaque formation, but... more Objectives—Inflammatory macrophage apoptosis is critical to atherosclerotic plaque formation, but its mechanisms remain enigmatic. We hypothesized that inhibitor of apoptosis protein (IAP) survivin regulates macrophage death in atherosclerosis. Methods and Results—Western blot analysis revealed discrete survivin expression in human aorta lipid streaks but virtually none in advanced atherosclerotic plaques, despite increased XIAP and cIAP2 levels. Survivin was detected in CD68-positive
Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metaboli... more Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of
Objective—To assess the association between secretory phospholipase A2 (sPLA2) activity, which en... more Objective—To assess the association between secretory phospholipase A2 (sPLA2) activity, which encompasses several types of sPLA2, and cardiovascular disease (CAD) in healthy individuals. Methods and Results—We investigated this association in a nested case-control study among the 25 663 participants in EPIC-Norfolk cohort. Cases (n991) were subjects in whom CAD developed during the 6 years of mean follow-up. Controls (n1806) matched
Different forms of mechanical stimulation are among the physiological factors constantly acting o... more Different forms of mechanical stimulation are among the physiological factors constantly acting on the vessel wall. We previously demonstrated that subjecting vascular smooth muscle cells (VSMCs) in culture to cyclic stretch increased the expression of high-molecular-weight caldesmon, a marker protein of a differentiated, contractile, VSMC phenotype. In the present work the effects of mechanical factors, in the form of circumferential
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